title: Identification of the NEDD4L gene as a prognostic marker by integrated microarray analysis of copy number and gene expression profiling in non-small cell lung cancer.
abstract: OBJECTIVE
  The purpose of this study was to identify prognostic genes by integrated microarray analysis between comparative genomic hybridization and gene expression with laser microdissection in non-small cell lung cancer (NSCLC).
  
  
  METHODS
  Integrated microarray analysis in 11 lung adenocarcinomas was performed, and several genes were identified. Among them, neural precursor cell-expressed developmentally down-regulated 4-like (NEDD4L) was chosen for further characterization. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was used to explore the clinicopathological significance of NEDD4L expression in 84 NSCLC patients.
  
  
  RESULTS
  18q was more frequently lost in advanced lung cancer. Therefore, we selected the NEDD4L gene, located on chromosome 18q, for which reduced expression was significantly correlated with copy number loss. NEDD4L mRNA expression in paired tumor/normal samples from 79 cases of lung cancer was evaluated using real-time PCR analysis. NEDD4L mRNA expression was significantly lower in tumor tissues than in normal lung tissues (p < 0.0001). Clinicopathological factors, such as excessive smoking history, histological grade (moderately and poorly), T stage (T2-4), lymph node metastasis, and pathological stage (stage II-IV), were significantly associated with low NEDD4L expression (p < 0.05). In the low expression group, prognoses were significantly poorer than in the high expression group (p < 0.05).
  
  
  CONCLUSIONS
  Low NEDD4L expression may be a marker of prognosis. This is the first report to describe NEDD4L expression in NSCLC. NEDD4L may be considered a key gene in the progression of NSCLC, and its expression is likely affected by genomic alterations.
authors.affiliation: Department of Molecular and Surgical Oncology, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sakashita
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inoue
authors.forename: Shinji
authors.initials: S
authors.lastname: Akamine
authors.forename: Teruyoshi
authors.initials: T
authors.lastname: Ishida
authors.forename: Naohiko
authors.initials: N
authors.lastname: Inase
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Shirao
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.forename: Koshi
authors.initials: K
authors.lastname: Mimori
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D016022:Case-Control Studies; D055028:Comparative Genomic Hybridization; D018450:Disease Progression; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D018628:Gene Dosage / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D061346:Laser Capture Microdissection; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D000075702:Nedd4 Ubiquitin Protein Ligases; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D056827:Endosomal Sorting Complexes Required for Transport; D012333:RNA, Messenger; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; C000618485:Nedd4L protein, human; D044767:Ubiquitin-Protein Ligases